DEF6

Chr 6AR

DEF6 guanine nucleotide exchange factor

Also known as: IBP, IMD87, SLAT, SWAP70L

NCBI Gene: 50619 ENSG00000023892 UniProt: Q01524

DEF6, or IBP, is a guanine nucleotide exchange factor (GEF) for RAC (MIM 602048) and CDC42 (MIM 116952) that is highly expressed in B and T cells (Gupta et al., 2003 [PubMed 12923183]).[supplied by OMIM, Mar 2008]

Primary Disease Associations & Inheritance

Immunodeficiency 87 and autoimmunityMIM #619573

Active trials

Pathogenic / LP

294

ClinVar variants

Pubs (1 yr)

3.0

Missense Z

0.26

LOEUF· LoF intolerant

Clinical Summary— DEF6

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Gene-Disease Validity (ClinGen)

immunodeficiency 87 and autoimmunity · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

7 Pathogenic / Likely Pathogenic· 95 VUS of 294 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.26LOEUF

pLI 0.998

Z-score 4.89

OE 0.11 (0.06–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.03Z-score

OE missense 0.56 (0.50–0.63)

208 obs / 372.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.11 (0.06–0.26)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.50–0.63)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84

0≤1.21.6

LoF obs/exp: 4 / 35.4Missense obs/exp: 208 / 372.3Syn Z: 1.57

0.5280th %ile

GOF

0.6833th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF57% of P/LP variants are LoF · LOEUF 0.26

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.